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J. Biol. Chem., Vol. 283, Issue 16, 10679-10689, April 18, 2008

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Characterization of a Novel Caenorhabditis elegans Prolyl 4-Hydroxylase with a Unique Substrate Specificity and Restricted Expression in the Pharynx and Excretory Duct^*

Katriina Keskiaho, Liisa Kukkola, Antony P. Page^¶, Alan D. Winter^¶, Jussi Vuoristo, Raija Sormunen^||, Ritva Nissi, Päivi Riihimaa, and Johanna Myllyharju¹

From the Collagen Research Unit, Department of Medical Biochemistry and Molecular Biology, Biocenter Oulu, and ^||Department of Pathology, University of Oulu, FIN-90014 Oulu, Finland and ^¶Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow G61 1QH, United Kingdom

Collagen prolyl 4-hydroxylases (C-P4Hs) have a critical role in collagen synthesis, since 4-hydroxyproline residues are necessary for folding of the triple-helical molecules. Vertebrate C-P4Hs are ₂β₂ tetramers in which the β subunit is identical to protein-disulfide isomerase (PDI). Three isoforms of the catalytic subunit, PHY-1, PHY-2, and PHY-3, have been characterized from Caenorhabditis elegans, PHY-1 and PHY-2 being responsible for the hydroxylation of cuticle collagens, whereas PHY-3 is predicted to be involved in collagen synthesis in early embryos. We have characterized transcripts of two additional C. elegans subunit-like genes, Y43F8B.4 and C14E2.4. Three transcripts were generated from Y43F8B.4, and a polypeptide encoded by one of them, named PHY-4.1, assembled into active (PHY-4.1)₂/(PDI-2)₂ tetramers and PHY-4.1/PDI-2 dimers when coexpressed with C. elegans PDI-2 in insect cells. The C14E2.4 transcript was found to have a frameshift leading to the absence of codons for two residues critical for P4H catalytic activity. Thus, C. elegans has altogether four functional C-P4H subunits, PHY-1, PHY-2, PHY-3, and PHY-4.1. The tetramers and dimers containing recombinant PHY-4.1 had a distinct substrate specificity from the other C-P4Hs in that they hydroxylated poly(L-proline) and certain other proline-rich peptides, including ones that are expressed in the pharynx, in addition to collagen-like peptides. These data and the observed restricted expression of the phy-4.1 transcript and PHY-4.1 polypeptide in the pharyngeal gland cells and the excretory duct suggest that in addition to collagens, PHY-4.1 may hydroxylate additional proline-rich proteins in vivo.

Received for publication, February 5, 2008

^* This work was supported by Health Science Council Grants 200471 and 202469 and Grant 44843 from the Finnish Centre of Excellence Programme 2000–2005 of the Academy of Finland and by the S. Juselius Foundation (to J. M.) and the Medical Research Council of Great Britain through the award of a Senior Fellowship (to A. P. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Collagen Research Unit, Dept. of Medical Biochemistry and Molecular Biology and Biocenter Oulu, P.O. Box 5000, University of Oulu, FIN-90014 Oulu, Finland. Tel.: 358-8-537-5740; Fax: 358-8-537-5811; E-mail: johanna.myllyharju{at}oulu.fi.

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